The present invention relates to a pharmaceutical composition for combined use of nitrogen mustard anticancer agents with anti-IL-6 receptor antibody for treatment of myeloma.
For chemotherapy of human tumors, alkylating agents, antimetabolites, antitumor antibiotics, platinum compounds and the like have been used. When single uses of these activating agents do not exhibit marked therapeutic effects, therapies in which multiple drugs are used in combination have been considered (Frei, E. III, Cancer Res. (1992) 32, 2593-2607). As anticancer agents that belong to the alkylating agents, there are mentioned nitrogen mustard anticancer agents, which is a general term used for the anticancer agents that have a partial structure called nitrogen mustard. Of the nitrogen mustard anticancer agents melphalan has been put into practical use.
IL-6 is a multifunctional cytokeine called B-cell stimulatory factor 2 or interferon xcex22. IL-6 was discovered as a differentiation factor responsible for activation of B-lymphocytes (Hirano, T. et al., Nature (1986) 324, 73-76). Thereafter, it was found to be a multifunctional cytokeine that influences the function of various cells (Akira, S. et al., Adv. in Immunology (1993) 54, 1-78). IL-6 imparts its biological activity through two proteins on the cell membrane.
One of them is a ligand-biding protein with a molecular weight of about 80 kD, IL-6 receptor, to which IL-6 binds. IL-6 receptor occurs not only in a membrane-bound form that penetrates and is expressed on the cell membrane but also as a soluble IL-6 receptor consisting mainly of the extracellular region. The other is non-ligand-binding gp130 with a molecular weight of about 130 kD that takes part in signal transmission. IL-6 and IL-6 receptor form a IL-6/IL-6 receptor complex, to which another membrane protein gp130 is bound, and thereby the biological activity of IL-6 is transmitted to the cell (Taga et al., J. Exp. Med. (1987) 166, 967).
Antibodies to IL-6 receptor (anti-IL-6 receptor antibodies) have been known (Novick D. et al., Hybridoma (1991) 10, 137-146 Huang, Y. W. et al., Hybridoma (1993) 12, 621-630 International Patent Application WO95-09873, French Patent Application FR 2694767, U.S. Pat. No. 5,216,128), one of which is PM-1 derived from mice (Hirata et al., J. Immunology (1989) 143, 2900-2906). Furthermore, a reshaped antibody obtained by replacing the complementarity determining regions (CDRs) of the mouse antibody with the CDRs of a human antibody has also been known.
However, the combined use of a nitrogen mustard anticancer agent and IL-6 receptor as a therapeutic agent for treatment of myeloma has not been known.
It is an object of the present invention to provide a new type of myeloma therapeutic agent that is more effective than the conventionally known myeloma therapeutic agents.
As a result of an intensive study to solve the above problems, the applicants have found that the combination of a nitrogen mustard anticancer agent, a conventionally known anticancer agent, and anti-IL-6 receptor antibody has a synergistic effect, i.e. it is more effective than the sole use of the nitrogen mustard anticancer agent or the sole use of anti-IL-6 receptor antibody for treatment of myeloma, and have completed the present invention.
Thus, the present invention provides a therapeutic agent for treatment of myeloma comprising anti-IL-6 receptor antibody for use in combination with a nitrogen mustard anticancer agent.
The present invention also provides a therapeutic agent for treatment of myeloma comprising anti-IL-6 receptor monoclonal antibody for use in combination with a nitrogen mustard anticancer agent.
The present invention also provides a therapeutic agent for treatment of myeloma comprising PM-1 antibody for use in combination with a nitrogen mustard anticancer agent.
The present invention also provides a therapeutic agent for treatment of myeloma comprising a reshaped PM-1 antibody for use in combination with a nitrogen mustard anticancer agent.
The present invention also provides a therapeutic agent for treatment of myeloma comprising anti-IL-6 receptor antibody for use in combination with mechlorethamine, nitrogen mustard N-oxide, melphalan, uramustin, ifosfamide, chlorambucil, or cyclophosphamide.
The present invention also provides a therapeutic agent for treatment of myeloma comprising a reshaped human PM-1 antibody for use in combination with melphalan.
The present invention also provides a therapeutic agent for treatment of myeloma comprising a nitrogen mustard anticancer agent for use in combination with anti-IL-6 receptor antibody.
The present invention also provides a therapeutic agent for treatment of myeloma comprising a nitrogen mustard anticancer agent for use in combination with anti-IL-6 receptor monoclonal antibody.
The present invention also provides a therapeutic agent for treatment of myeloma comprising a nitrogen mustard anticancer agent for use in combination with PM-1 antibody.
The present invention also provides a therapeutic agent for treatment of myeloma comprising a nitrogen mustard anticancer agent for use in combination with a reshaped human PM-1 antibody.
The present invention also provides a therapeutic agent for treatment of myeloma comprising mechlorethamine, nitrogen mustard N-oxide, melphalan, uramustin, ifosfamide, chlorambucil, or cyclophosphamide in combination with anti-IL-6 receptor antibody.
The present invention also provides a therapeutic agent for treatment of myeloma comprising melphalan for use in combination with a reshaped human PM-1 antibody.
The present invention also provides a therapeutic agent for treatment of myeloma comprising a nitrogen mustard anticancer agent and anti-IL-6 receptor antibody.
The present invention also provides a therapeutic agent for treatment of myeloma comprising a nitrogen mustard anticancer agent and anti-IL-6 receptor monoclonal antibody.
The present invention also provides a therapeutic agent for treatment of myeloma comprising a nitrogen mustard anticancer agent and PM-1 antibody.
The present invention also provides a therapeutic agent for treatment of myeloma comprising a nitrogen mustard anticancer agent and a reshaped human PM-1 antibody.
The present invention also provides a therapeutic agent for treatment of myeloma comprising mechlorethamine, nitrogen mustard N-oxide, melphalan, uramustin, ifosfamide, chlorambucil, or cyclophosphamide and anti-IL-6 receptor antibody.
The present invention provides a therapeutic agent for treatment of myeloma comprising melphalan and a reshaped human PM-1 antibody.